Of the nearly 150,000 patients diagnosed with advanced non-small cell lung cancer each year, approximately 10% have an initial response to the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI) erlotinib or gefitinib. These patients are likely to have evidence of dependence on the EGFR pathway, specifically either mutations in or increased copy number of the epidermal growth factor receptor (EGFR) gene. While these patients have an initial response to treatment with erlotinib or gefitinib, these patients develop acquired resistance to these drugs in a median of 12-13 months. We and others have demonstrated that tumors from patients with acquired resistance to erlotinib and gefitinib commonly have a second site mutation in EGFR, a T790M, which when studied in vitro is associated with resistance to treatment with erlotinib and gefitinib. Initial work using dasatinib in cell culture models of acquired resistance suggest that this agent, a multi-targeted tyrosine kinase inhibitor, may have anti-tumor activity in patients with acquired resistance to erlotinib or gefitinib. We propose to test the hypothesis that, in patients with lung adenocarcinoma who have developed acquired resistance to erlotinib or gefitinib, treatment with dasatinib will lead to a decrease in size of tumors. The specific aims of the proposal are (Aim 1) To determine the response rate of dasatinib in patients with lung adenocarcinoma with acquired resistance to gefitinib or erlotinib, and (Aim 2) To determine the toxicity profile of dasatinib in patients with lung adenocarcinoma with acquired resistance to gefitinib or erlotinib. To address these aims, we propose to initiate a phase 2 trial of dasatinib in patients with lung adenocarcinoma and acquired resistance to erlotinib or gefitinib. Non-small cell lung cancer (NSCLC) is the leading cause of cancer death in men and women in the United States, killing more than 150,000 patients each year. While approximately 10% of patients with NSCLC initially respond to treatment with erlotinib or gefitinib, these patients eventually develop acquired resistance to erlotinib or gefitinib. The proposed work is a clinical trial to determine whether dasatinib is an effective treatment for patients with NSCLC and acquired resistance to erlotinib or gefitinib. [unreadable] [unreadable] [unreadable]